In the field of the cosmetics industry there is an increasing need for agents for lightening skin and hair and for agents for combating age spots. In this context, cosmetics for lightening skin and hair and for combating age spots play a major role in particular in Asiatic countries with a dark skinned/haired population, but agents for such cosmetic treatments are gaining in importance in the central European area and in the USA as well.
The skin and hair colour of people is essentially determined via the melanocyte count, by the melanin concentration and the intensity of the melanin biosynthesis, in which context, on the one hand, intrinsic factors such as the genetic make-up of an individual and, on the other hand, extrinsic factors such as, in particular, the intensity and frequency of exposure to UV exert a significant influence on the skin and hair colour.
Skin-lightening active compounds usually intervene in the melanin metabolism or catabolism. The melanin pigments, which as a rule are brown to black in colour, are formed in the melanocytes of the skin, transferred into the keratinocytes and give rise to the colouration of the skin or the hair. In mammals, the brown-black eumelanins are formed mainly from hydroxy-substituted aromatic amino acids such as L-tyrosine and L-DOPA and the yellow to red pheomelanins are additionally formed from sulphur-containing molecules (Cosmetics & Toiletries 1996, 111 (5), 43-51). Starting from L-tyrosine, L-3,4-dihydroxyphenylalanine (L-DOPA) is formed by the copper-containing key enzyme tyrosinase, which L-3,4-dihydroxyphenylalanine, in turn, is converted by tyrosinase to dopachrome. The latter is oxidised to melanin via several steps catalysed by various enzymes.
Skin-lightening agents are used for various reasons: if the melanin-forming melanocytes in the human skin are not uniformly distributed for whatever reason, pigment spots are produced that are either lighter or darker than the surrounding areas of the skin. In order to eliminate this problem, lightening agents are used that help at least partially to even out such pigment spots. In addition, for many people there is a need to lighten their naturally dark skin colour or to prevent skin pigmentation. Very reliable and effective skin and hair lightening agents are needed for this purpose. Many skin and hair lightening agents contain tyrosinase inhibitors that are more or less powerful. However, this is only one possible route for skin and hair lightening.
Occasionally, UV-absorbing substances are also used for protection against the increase in skin pigmentation induced by UV light. However, this is an effect of purely physical origin and thus differs from the biological action of skin lightening agents on the cellular melanin formation, which is detectable even in the absence of UV light. Specifically, only the UV-induced browning of the skin can be prevented by UV filters, in contrast to which a lightening of the skin can also be produced by biologically active skin lighteners, which intervene in the melanin biosynthesis.
Hydroquinone, hydroquinone derivatives, such as, for example, arbutin, vitamin C, derivatives of ascorbic acid, such as, for example, ascorbyl palmitate, kojic acid and derivatives of kojic acid, such as, for example, kojic acid dipalmitate, are used in particular in commercially available skin and hair lightening agents.
One of the skin and hair lightening agents most frequently used is hydroquinone. However, the substance has a cytotoxic effect on melanocytes and acts as an irritant on the skin. Therefore, for example in Europe, Japan and South Africa, such preparations are no longer permissible for cosmetic applications. Moreover, hydroquinone is highly sensitive to oxidation and can be stabilised in cosmetic formulations only with difficulty.
Vitamin C and ascorbic acid derivatives have only an inadequate action on the skin. Moreover, they do not act directly as tyrosinase inhibitors, but reduce the coloured intermediates in the melanin biosynthesis.
Kojic acid (5-hydroxy-2-hydroxymethyl-4-pyranone) is a tyrosinase inhibitor that inhibits the catalytic action thereof via chelation of the copper atoms of the enzyme; it is used in commercial skin and hair lightening agents, but has a high sensitising potential and causes contact allergies.
In the search for novel agents that have a skin and hair lightening action and/or are active against age spots, the aim is, accordingly, quite generally to find substances that inhibit the enzyme tyrosinase in as low a concentration as possible, it furthermore having to be taken into account that these substances used in cosmetic and/or pharmaceutical products, in addition to having a high activity at concentrations that are as low as possible, must also be                toxicologically acceptable,        readily tolerated by the skin and in particular not sensitising and not irritant,        stable (in particular in the customary cosmetic and/or pharmaceutical formulations),        preferably odourless and        able to be produced inexpensively (that is to say using standard methods and/or starting from standard precursors).        
The search for suitable (active) substances that have one or more of the said properties to an adequate degree is made more difficult for the person skilled in the art because there is no clear dependence between the chemical structure of a substance, on the one hand, and its biological activity and its stability, on the other hand. Furthermore, there is no predictable relationship between the skin lightening effect, the toxicological acceptability, the tolerance by the skin and/or the stability of potential active compounds. Furthermore, a particular prerequisite for the use of an active substance in practice is its stability to chemical substances which are customarily used as accompanying constituents in cosmetics and to light.